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Obesity is associated with increased risk and worse prognosis of many tumours including those of the breast and of the esophagus. Adipokines released from the peritumoural adipose tissue promote the metastatic potential of cancer cells, suggesting the existence of a crosstalk between the adipose tissue and the surrounding tumour. Mitochondrial Ca2+ signaling contributes to the progression of carcinoma of different origins. However, whether adipocyte-derived factors modulate mitochondrial Ca2+ signaling in tumours is unknown. Here, we show that conditioned media derived from adipose tissue cultures (ADCM) enriched in precursor cells impinge on mitochondrial Ca2+ homeostasis of target cells. Moreover, in modulating mitochondrial Ca2+ responses, a univocal crosstalk exists between visceral adipose tissue-derived preadipocytes and esophageal cancer cells, and between subcutaneous adipose tissue-derived preadipocytes and triple-negative breast cancer cells. An unbiased metabolomic analysis of ADCM identified creatine and creatinine for their ability to modulate mitochondrial Ca2+ uptake, migration and proliferation of esophageal and breast tumour cells, respectively.
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Tejido Adiposo , Neoplasias , Humanos , Tejido Adiposo/patología , Adipocitos , Obesidad/complicaciones , Grasa Subcutánea/patología , Neoplasias/patologíaRESUMEN
OBJECTIVE: The serine protease inhibitor SerpinB3 has been described as critical mediator of liver fibrosis and it has been recently proposed as an additional hepatokine involved in NASH development and insulin resistance. Protease Activated Receptor 2 has been identified as a novel regulator of hepatic metabolism. A targeted therapeutic strategy for NASH has been investigated, using 1-Piperidine Propionic Acid (1-PPA), since this compound has been recently proposed as both Protease Activated Receptor 2 and SerpinB3 inhibitor. METHODS: The effect of SerpinB3 on inflammation and fibrosis genes was assessed in human macrophage and stellate cell lines. Transgenic mice, either overexpressing SerpinB3 or carrying Serpinb3 deletion and their relative wild type strains, were used in experimental NASH models. Subgroups of SerpinB3 transgenic mice and their controls were also injected with 1-PPA to assess the efficacy of this compound in NASH inhibition. RESULTS: 1-PPA did not present significant cell and organ toxicity and was able to inhibit SerpinB3 and PAR2 in a dose-dependent manner. This effect was associated to a parallel reduction of the synthesis of the molecules induced by endogenous SerpinB3 or by its paracrine effects both in vitro and in vivo, leading to inhibition of lipid accumulation, inflammation and fibrosis in experimental NASH. At mechanistic level, the antiprotease activity of SerpinB3 was found essential for PAR2 activation, determining upregulation of the CCAAT Enhancer Binding Protein beta (C/EBP-ß), another pivotal regulator of metabolism, inflammation and fibrosis, which in turn determined SerpinB3 synthesis. CONCLUSIONS: 1-PPA treatment was able to inhibit the PAR2 - C/EBP-ß - SerpinB3 axis and to protect from NASH development and progression, supporting the potential use of a similar approach for a targeted therapy of NASH.
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Enfermedad del Hígado Graso no Alcohólico , Ratones , Animales , Humanos , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Receptor PAR-2 , Proteína beta Potenciadora de Unión a CCAAT , Cirrosis Hepática/tratamiento farmacológico , Ratones Transgénicos , InflamaciónRESUMEN
Epidemiological observations, experimental studies and clinical data show that obesity is associated with a higher risk of developing different types of cancer; however, proof of a cause-effect relationship that meets the causality criteria is still lacking. Several data suggest that the adipose organ could be the protagonist in this crosstalk. In particular, the adipose tissue (AT) alterations occurring in obesity parallel some tumour behaviours, such as their theoretically unlimited expandability, infiltration capacity, angiogenesis regulation, local and systemic inflammation and changes to the immunometabolism and secretome. Moreover, AT and cancer share similar morpho-functional units which regulate tissue expansion: the adiponiche and tumour-niche, respectively. Through direct and indirect interactions involving different cellular types and molecular mechanisms, the obesity-altered adiponiche contributes to cancer development, progression, metastasis and chemoresistance. Moreover, modifications to the gut microbiome and circadian rhythm disruption also play important roles. Clinical studies clearly demonstrate that weight loss is associated with a decreased risk of developing obesity-related cancers, matching the reverse-causality criteria and providing a causality correlation between the two variables. Here, we provide an overview of the methodological, epidemiological and pathophysiological aspects, with a special focus on clinical implications for cancer risk and prognosis and potential therapeutic interventions.
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Obesity and insulin resistance (IR), the key features of metabolic syndrome, are closely associated with a state of chronic, low-grade inflammation. Bariatric surgery leads to a considerable reduction in the adipose tissue mass and systemic inflammation along with a reduction of IR, with a whole-body metabolic improvement. However, a sizable portion of people experience an IR relapse within few years of remission.Numerous studies have attempted to explore the best clinical predictors of the improvement of insulin sensitivity and the maintenance of glucose homeostasis after bariatric surgery, but no simple fasting blood test has been found to be effective in predicting the short and long-term beneficial effects on glycaemia.With the present study, we investigated T-cell and antibody responses against CD300e, an antigen highly expressed in the adipose tissue of patients with obesity before the bariatric surgery-induced weight loss. We found both in fat tissue and in peripheral blood anti-CD300e-specific T helper 1 responses. Moreover, we evidenced in the sera of individuals with obesity an antibody response towards CD300e and revealed the existence of a significant correlation between the level of antibodies before surgery and the maintenance of glucose control after the intervention.
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The knowledge of the molecular landscape of ileal neuroendocrine tumors (NETs) is affected by the lack of systematic studies investigating intra-tumoral heterogeneity. In this study, intra-tumoral heterogeneity was investigated in 27 primary ileal G1-NETs and their matched nodal and liver metastases in order to assess the tumor grading, the expression status of two somatostatin receptor isoforms (i.e. SSTR2A and SSTR5) and mTOR signaling dysregulation (ph-mTOR, ph-p70S6K, ph-4EBP1, PTEN and miR-21). Among the 27 G1 primary tumors, 4 shifted to G2 in the matched liver metastasis. Although mTOR activation was pretty consistent between primary and secondary malignancies, mTOR effectors (ph-p70S6K and ph-4EBP1) were overexpressed in matched liver metastases, whereas PTEN expression profile changed in only two cases. MiR-21 was significantly up-regulated in the metastatic setting. Although SSTRs expression was present in most of the primary tumors and matched metastasis, we found SSTR5 expression to be significantly increased in liver metastases. Notably, SSTRs expression was heterogeneous within the same lesions in most of the lesions. Overall, despite primary and metastatic ileal NETs show a similar molecular landscape, tumor grading and mTOR signaling pathway may diverge in the metastatic setting, thus affecting prognosis and treatment.
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Neoplasias Hepáticas , MicroARNs , Tumores Neuroendocrinos , Humanos , Neoplasias Hepáticas/metabolismo , MicroARNs/genética , Tumores Neuroendocrinos/patología , Receptores de Somatostatina/genética , Proteínas Quinasas S6 Ribosómicas 70-kDa , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
OPINION STATEMENT: The clinical scenario of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) is continuously changing due to significant improvements in the definition of their molecular landscapes and the introduction of innovative therapeutic approaches. Many efforts are currently employed in the integration of the genetics/epigenetics and clinical information. This is leading to an improvement of tumor classification, prognostic stratification and ameliorating the management of patients based on a personalized approach.
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Neoplasias Gastrointestinales/terapia , Tumores Neuroendocrinos/terapia , Medicina de Precisión , Biomarcadores de Tumor , Toma de Decisiones Clínicas , Terapia Combinada , Diagnóstico por Imagen/métodos , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Neoplasias Gastrointestinales/diagnóstico , Neoplasias Gastrointestinales/etiología , Neoplasias Gastrointestinales/mortalidad , Humanos , Imagen Multimodal/métodos , Tumores Neuroendocrinos/diagnóstico , Tumores Neuroendocrinos/etiología , Tumores Neuroendocrinos/mortalidad , Medicina de Precisión/métodos , Pronóstico , Resultado del TratamientoRESUMEN
CONTEXT: Melanocortin receptor-4 (MC4R) gene mutations are associated with early-onset severe obesity, and the identification of potential pathological variants is crucial for the clinical management of patients with obesity. OBJECTIVE: To explore whether and how a novel heterozygous MC4R variant (MC4R-F313Sfs*29), identified in a young boy (body mass index [BMI] 38.8 kg/m2) during a mutation analysis conducted in a cohort of patients with obesity, plays a determinant pathophysiological role in the obesity development. DESIGN SETTING AND PATIENTS: The genetic screening was carried out in a total of 209 unrelated patients with obesity (BMIâ¯≥â¯35â¯kg/m2). Structural and functional characterization of the F313Sfs*29-mutated MC4R was performed using computational approaches and in vitro, using HEK293 cells transfected with genetically encoded biosensors for cAMP and Ca2+. RESULTS: The F313Sfs*29 was the only variant identified. In vitro experiments showed that HEK293 cells transfected with the mutated form of MC4R did not increase intracellular cAMP or Ca2+ levels after stimulation with a specific agonist in comparison with HEK293 cells transfected with the wild type form of MC4R (∆R/R0â =â -90% ± 8%; Pâ <â 0.001). In silico modeling showed that the F313Sfs*29 mutation causes a major reorganization in the cytosolic domain of MC4R, thus reducing the affinity of the putative GalphaS binding site. CONCLUSIONS: The newly discovered F313Sfs*29 variant of MC4R may be involved in the impairment of α-MSH-induced cAMP and Ca2+ signaling, blunting intracellular G protein-mediated signal transduction. This alteration might have led to the dysregulation of satiety signaling, resulting in hyperphagia and early onset of obesity.
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Obesidad Mórbida/genética , Receptor de Melanocortina Tipo 4/genética , Adolescente , Adulto , Edad de Inicio , Niño , Estudios de Cohortes , Análisis Mutacional de ADN , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Gráficos de Crecimiento , Células HEK293 , Humanos , Italia/epidemiología , Mutación con Pérdida de Función/genética , Masculino , Persona de Mediana Edad , Modelos Moleculares , Obesidad Mórbida/epidemiología , Obesidad Infantil/epidemiología , Obesidad Infantil/genética , Receptor de Melanocortina Tipo 4/químicaRESUMEN
BACKGROUND: Vascular endothelial growth factor (VEGF) is a subfamily of growth factors involved in angiogenesis; CD34+ cells are normally found in endothelial progenitor cells and endothelial cells of blood vessels. Colonic adenomatous polyps may not always be completely removable endoscopically, and a preoperative diagnosis might still be necessary. The aim of the study was to evaluate whether VEGF-A, VEGF-C and CD34 mRNA expression along colorectal carcinogenesis steps can implement NICE (Narrow-Band Imaging International Colorectal Endoscopic) classification in the diagnosis of malignancy in colorectal polypoid lesions. METHODS: Seventy-one subjects with colonic adenoma or cancer who underwent screening narrow-band imaging (NBI) colonoscopy were prospectively enrolled in the MICCE1 project (Treviso center). Polyps were classified according to the NICE classification. Real-time RT-PCR for VEGF-A, VEGF-C and CD34 mRNA expression was performed. Nonparametric statistics, receiver-operating characteristic curve analysis and logistic multiple regression analysis were used. RESULTS: VEGF-A and CD34 mRNA expression was significantly higher in sessile adenomas than in polypoid ones (p < 0.001 and p = 0.01, respectively). VEGF-A, VEGF-C and CD34 mRNA expression was significantly higher in adenocarcinoma than in adenoma (p = 0.01, p = 0.01 and p = 0.01, respectively). The accuracy of VEGF-A, VEGF-C and CD34 mRNA expression for prediction of malignancy was 0.79 (95% CI 0.65-0.90), 0.81 (95% CI 0.66-0.91) and 0.80 (95% CI 0.65-0.90), respectively, while the accuracy of the NICE classification was 0.85 (95% CI 0.72-0.94). The determination coefficient R2, which indicates the amount of the variability explained by a regression model, for NICE classification alone was 0.24 (p < 0.001). A regression model that included NICE classification and VEGF-C mRNA expression showed an R2 = 0.39 as well as a model including NICE classification and CD34 mRNA levels. CONCLUSIONS: This study demonstrated that VEGF-C and CD34 mRNA levels might be useful to stratify colorectal polyps in different risk of progression classes by implementing the accuracy of the NICE classification. Studies on in vivo detection of these markers are warranted.
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Adenocarcinoma/metabolismo , Antígenos CD34/metabolismo , Neoplasias del Colon/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor C de Crecimiento Endotelial Vascular/metabolismo , Adenocarcinoma/diagnóstico por imagen , Adenoma/diagnóstico por imagen , Adenoma/metabolismo , Biomarcadores de Tumor/metabolismo , Neoplasias del Colon/diagnóstico por imagen , Colonoscopía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Imagen de Banda Estrecha , Neovascularización Patológica , Estudios ProspectivosRESUMEN
CD300e is a surface receptor, expressed by myeloid cells, involved in the tuning of immune responses. CD300e engagement was reported to provide the cells with survival signals, to trigger the expression of activation markers and the release of pro-inflammatory cytokines. Hence, CD300e is considered an immune activating receptor. In this study, we demonstrate that the ligation of CD300e in monocytes hampers the expression of the human leukocyte antigen (HLA) class II, affecting its synthesis. This effect, which is associated with the transcription impairment of the signal transducer and activator of transcription 1 (STAT1), overcomes the capacity of interferon gamma (IFN-γ) to promote the expression of the antigen-presenting molecules. Importantly, the decreased expression of HLA-II on the surface of CD300e-activated monocytes negatively impacts their capacity to activate T cells in an antigen-specific manner. Notably, unlike in vitro- differentiated macrophages which do not express CD300e, the immune receptor is expressed by tissue macrophages. Taken together, our findings argue against the possibility that this molecule should be considered an activating immune receptor sensu stricto. Moreover, our results support the notion that CD300e might be a new player in the regulation of the expansion of T cell-mediated responses.
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Activación de Linfocitos/inmunología , Receptores Inmunológicos/metabolismo , Factor de Transcripción STAT1/metabolismo , Presentación de Antígeno/inmunología , Línea Celular , Citocinas/metabolismo , Antígenos HLA/metabolismo , Voluntarios Sanos , Humanos , Interferón gamma/metabolismo , Monocitos/metabolismo , Transducción de Señal , Linfocitos T/inmunologíaRESUMEN
Background: Esophageal cancer is an aggressive tumor, with poor prognosis and low survival rates. Although diagnosis and treatment have improved considerably, more efficient prognostic factors are urgently needed to prevent postoperative recurrence and metastasis. Cancer stem cells are key players in tumor progression and several studies have investigated the association between the expression of stemness genes and clinical outcome. However, the prognostic value of stemness markers in esophageal cancer remains controversial. We identified six factors involved in angiogenesis, anti-apoptosis and self-renewal that have been associated to poor prognosis in other types of cancer. We conducted a review of the literature and a meta-analysis to assess their potential prognostic role in this malignancy. Material and Methods: The database of PMC, PubMed, Web of Science, Embase and The Cochrane Library were searched to investigate the association between CD34, CD133, Nucleostemin, OCT-4, NANOG and CD90, and the survival of patients affected by esophageal squamous cell carcinoma or esophageal adenocarcinoma. Among the 615 eligible studies, a total of 19 articles (including 1586 patients) met the inclusion criteria for the meta-analysis, and the pooled hazard ratio and 95% confidence intervals were calculated. Results: Data showed that high expression of CD34 (HR 2.10; 95%CI 1.41-3.14; I2=56%; p=0.0003), CD133 (HR 1.91; 95%CI 1.15-3.19; I2=55%; p=0.01) and Nucleostemin (HR 2.97; 95%CI 1.11-7.98; I2=0%; p=0.03) were associated with poor prognosis in patients affected by esophageal cancer. The expression of NANOG and OCT-4 showed no significant association with survival of patients, whereas no study involving CD90 was included in this meta-analysis. Conclusion: CD34, CD133 and Nucleostemin might represent useful prognostic markers in patients affected by esophageal cancer.
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Squamous cell carcinoma antigen-1 (SCCA1) overexpression is associated with poor prognosis and chemoresistance in several tumor types, however, the underlying mechanisms remain elusive. Here, we report SCCA1 in relation to the immune and peritumoral adipose tissue microenvironment in early and advanced esophageal adenocarcinoma (EAC). In our series of patients with EAC, free SCCA1 serum levels were associated with significantly worse overall survival, and SCCA1-IgM serum levels showed a trend to a worse overall survival. Serum SCCA1 and intratumoral SCCA1 were inversely correlated with immune activation markers. In agreement with these findings, SCCA1 induced the expression of the immune checkpoint molecule programmed death ligand-1 on monocytes and a direct correlation of these 2 molecules was observed in sequential tumor sections. Furthermore, SCCA1 mRNA expression within the tumor was inversely correlated with stem cell marker expression both within the tumor and in the peritumoral adipose tissue. In vitro, in EAC cell lines treated with different chemotherapeutic drugs, cell viability was significantly modified by SCCA1 presence, as cells overexpressing SCCA1 were significantly more resistant to cell death. In conclusion, poor prognosis in EAC overexpressing SCCA1 is due to reduced tumor chemosensitivity as well as intratumoral immunity impairment, likely induced by this molecule.
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Adenocarcinoma/metabolismo , Antígenos de Neoplasias/sangre , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Resistencia a Antineoplásicos , Neoplasias Esofágicas/metabolismo , Serpinas/sangre , Adenocarcinoma/genética , Anciano , Antígenos de Neoplasias/genética , Antineoplásicos/farmacología , Línea Celular Tumoral , Supervivencia Celular , Neoplasias Esofágicas/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Serpinas/genética , Análisis de Supervivencia , Regulación hacia ArribaRESUMEN
AIMS: In hepatocellular carcinoma (HCC), the regulatory protease Dipeptidyl-peptidase IV (DPPIV/CD26), that possesses pro-apoptotic properties, has been found abnormally regulated. The protease inhibitor SerpinB3, exerting anti-apoptotic activity, has also been described to be upregulated, especially in HCCs with poor prognosis. The aim of this study was to investigate the possible relationship between these two molecules in HCC patients and in experimental models. MATERIALS AND METHODS: DPPIV/CD26 and SerpinB3 expression was measured in liver specimens of 67 patients with HCC. HepG2 and Huh7 cells, stably transfected to overexpress SerpinB3, and respective control cells were used to assess biological and metabolic modifications of DPPIV/CD26 activity induced by this serpin. KEY FINDINGS: DPPIV/CD26 and SerpinB3 were localized in the same tumoral areas and both molecules were correlated with the grade of tumor differentiation, with the highest values detected in GI tumors. Cell lines over-expressing SerpinB3 displayed upregulation of DPPIV/CD26, likely as a feedback mechanism, due to the DPPIV/CD26 protease activity inhibition by SerpinB3, as confirmed by the similar behavior induced by the inhibitor Sitagliptin. Moreover, they exhibited lower glycogen storage and higher lipid accumulation, typical effects of DPPIV/CD26. SIGNIFICANCE: A close connection between SerpinB3 and DPPPIV has been identified, but further studies are required to better understand the mechanism by which these proteins communicate and exert metabolic effects in HCC.
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Antígenos de Neoplasias/metabolismo , Carcinoma Hepatocelular/metabolismo , Dipeptidil Peptidasa 4/biosíntesis , Regulación Enzimológica de la Expresión Génica , Neoplasias Hepáticas/metabolismo , Proteínas de Neoplasias/metabolismo , Serpinas/metabolismo , Anciano , Carcinoma Hepatocelular/patología , Femenino , Regulación Neoplásica de la Expresión Génica , Glucógeno/metabolismo , Células Hep G2 , Humanos , Metabolismo de los Lípidos/efectos de los fármacos , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Fosfato de Sitagliptina/farmacologíaRESUMEN
Peritumoral microenvironment affects cancer development and chemoresistance, and visceral adipose tissue may play a critical role. We aimed to identify depot-specific adipose characteristics associated with carcinogenesis and resistance to neoadjuvant therapy in esophageal adenocarcinoma (EAC). We analyzed: (i) the peritumoral adipose tissue of rats following the induction of esophageal carcinogenesis; (ii) the peritumoral and distal (omental) adipose tissue of patients affected by EAC; (iii) adipose-derived stem cells (ADSC) isolated from healthy patients and treated with conditioned medium (CM), collected from tumoral and adipose tissue of patients with EAC. In peritumoral adipose tissue of rats, CD34, CD31 and vascular endothelial growth factor (VEGF) expression increased progressively during EAC development. In patients with EAC, expression of CD34, CD45, CD90 and nucleostemin (NSTM) was higher in peritumoral than in distal adipose tissue and decreased in the presence of neoadjuvant therapy. Moreover, expression of NSTM, octamer-binding transcription factor 4 (OCT-4) and VEGF was higher in peritumoral (but not in distal) adipose tissue of chemoresistant patients. In ADSC, treatment with peritumoral adipose tissue CM increased the adipogenic potential and the expression of CD34, CD90, NSTM and OCT-4. These effects were similar to those induced by cancer-derived CM, but were not observed in ADSC treated with distal adipose tissue CM and were partially reduced by a leptin antagonist. Last, ADSC treated with peritumoral CM of chemoresistant patients displayed increased expression of NSTM, OCT-4, leptin, leptin receptor, alpha-smooth muscle actin (α-SMA), CD34 and VEGF. These results suggest that peritumoral adipose tissue may promote, by paracrine signaling, the expression of depot-specific factors associated with therapeutic resistance.
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Adenocarcinoma/patología , Tejido Adiposo/patología , Resistencia a Antineoplásicos/fisiología , Neoplasias Esofágicas/patología , Microambiente Tumoral/fisiología , Adenocarcinoma/metabolismo , Anciano , Animales , Neoplasias Esofágicas/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Comunicación Paracrina/fisiología , Ratas , Ratas Sprague-DawleyRESUMEN
Obesity is associated with cancer risk in esophageal adenocarcinoma (EAC). Adipose tissue directly stimulates tumor progression independently from body mass index (BMI), but the mechanisms are not fully understood. We studied the morphological, histological and molecular characteristics of peritumoral and distal adipose tissue of 60 patients with EAC, to investigate whether depot-specific differences affect tumor behavior. We observed that increased adipocyte size (a hallmark of obesity) was directly associated with leptin expression, angiogenesis (CD31) and lymphangiogenesis (podoplanin); however, these parameters were associated with nodal metastasis only in peritumoral but not distal adipose tissue of patients. We treated OE33 cells with conditioned media (CM) collected from cultured biopsies of adipose tissue and we observed increased mRNA levels of leptin and adiponectin receptors, as well as two key regulator genes of epithelial-to-mesenchymal transition (EMT): alpha-smooth muscle actin (α-SMA) and E-cadherin. This effect was greater in cells treated with CM from peritumoral adipose tissue of patients with nodal metastasis and was partially blunted by a leptin antagonist. Therefore, peritumoral adipose tissue may exert a direct effect on the progression of EAC by secreting depot-specific paracrine factors, and leptin is a key player in this crosstalk.
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Adenocarcinoma/metabolismo , Tejido Adiposo/metabolismo , Neoplasias Esofágicas/metabolismo , Obesidad/metabolismo , Comunicación Paracrina , Actinas/genética , Actinas/metabolismo , Adenocarcinoma/complicaciones , Adenocarcinoma/genética , Adenocarcinoma/secundario , Adenocarcinoma/terapia , Adipocitos/metabolismo , Adipocitos/patología , Tejido Adiposo/patología , Anciano , Antígenos CD , Cadherinas/genética , Cadherinas/metabolismo , Tamaño de la Célula , Medios de Cultivo Condicionados/metabolismo , Transición Epitelial-Mesenquimal , Neoplasias Esofágicas/complicaciones , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/terapia , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Leptina/genética , Leptina/metabolismo , Linfangiogénesis , Metástasis Linfática , Masculino , Glicoproteínas de Membrana/metabolismo , Persona de Mediana Edad , Neovascularización Patológica , Obesidad/complicaciones , Obesidad/genética , Obesidad/patología , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , ARN Mensajero/metabolismo , Receptores de Adiponectina/genética , Receptores de Adiponectina/metabolismo , Transducción de Señal , Técnicas de Cultivo de Tejidos , Células Tumorales CultivadasRESUMEN
Insulin resistance and obesity are associated with a reduction of mitochondrial content in various tissues of mammals. Moreover, a reduced nitric oxide (NO) bioavailability impairs several cellular functions, including mitochondrial biogenesis and insulin-stimulated glucose uptake, two important mechanisms of body adaptation in response to physical exercise. Although these mechanisms have been thoroughly investigated in skeletal muscle and heart, few studies have focused on the effects of exercise on mitochondria and glucose metabolism in adipose tissue. In this study, we compared the in vivo effects of chronic exercise in subcutaneous adipose tissue of wild-type (WT) and endothelial NO synthase (eNOS) knockout (eNOS(-/-)) mice after a swim training period. We then investigated the in vitro effects of NO on mouse 3T3-L1 and human subcutaneous adipose tissue-derived adipocytes after a chronic treatment with an NO donor: diethylenetriamine-NO (DETA-NO). We observed that swim training increases mitochondrial biogenesis, mitochondrial DNA content, and glucose uptake in subcutaneous adipose tissue of WT but not eNOS(-/-) mice. Furthermore, we observed that DETA-NO promotes mitochondrial biogenesis and elongation, glucose uptake, and GLUT4 translocation in cultured murine and human adipocytes. These results point to the crucial role of the eNOS-derived NO in the metabolic adaptation of subcutaneous adipose tissue to exercise training.
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Tejido Adiposo/metabolismo , Regulación Enzimológica de la Expresión Génica/fisiología , Glucosa/metabolismo , Mitocondrias/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Condicionamiento Físico Animal/fisiología , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Animales , Línea Celular , Humanos , Masculino , Ratones , Ratones Noqueados , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo III/genética , Norepinefrina , NataciónRESUMEN
Endurance exercise training increases cardiac energy metabolism through poorly understood mechanisms. Nitric oxide (NO) produced by endothelial NO synthase (eNOS) in cardiomyocytes contributes to cardiac adaptation. Here we demonstrate that the NO donor diethylenetriamine-NO (DETA-NO) activated mitochondrial biogenesis and function, as assessed by upregulated peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), nuclear respiratory factor 1, and mitochondrial transcription factor A (Tfam) expression, and by increased mitochondrial DNA content and citrate synthase activity in primary mouse cardiomyocytes. DETA-NO also induced mitochondrial biogenesis and function and enhanced both basal and insulin-stimulated glucose uptake in HL-1 cardiomyocytes. The DETA-NO-mediated effects were suppressed by either PGC-1α or Tfam small-interference RNA in HL-1 cardiomyocytes. Wild-type and eNOS(-/-) mice were subjected to 6 wk graduated swim training. We found that eNOS expression, mitochondrial biogenesis, mitochondrial volume density and number, and both basal and insulin-stimulated glucose uptake were increased in left ventricles of swim-trained wild-type mice. On the contrary, the genetic deletion of eNOS prevented all these adaptive phenomena. Our findings demonstrate that exercise training promotes eNOS-dependent mitochondrial biogenesis in heart, which behaves as an essential step in cardiac glucose transport.
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Adaptación Fisiológica/fisiología , Metabolismo de los Hidratos de Carbono/fisiología , Glucosa/metabolismo , Recambio Mitocondrial/fisiología , Miocardio/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Condicionamiento Físico Animal/fisiología , Adaptación Fisiológica/efectos de los fármacos , Animales , Metabolismo de los Hidratos de Carbono/efectos de los fármacos , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Corazón/efectos de los fármacos , Proteínas del Grupo de Alta Movilidad/genética , Proteínas del Grupo de Alta Movilidad/metabolismo , Ratones , Ratones Noqueados , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Recambio Mitocondrial/efectos de los fármacos , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Óxido Nítrico Sintasa de Tipo III/genética , Factor Nuclear 1 de Respiración/genética , Factor Nuclear 1 de Respiración/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Triazenos/farmacologíaRESUMEN
BACKGROUND: Esophageal adenocarcinoma is often associated with obesity, and a 5 Kg m(-2) increase in body mass index (BMI) has, in fact, been found to be strongly associated with the risk of this type of cancer (RR, 1.52; p < 0.0001). Esophagectomy with lymphoadenectomy is the mainstay of therapy for these patients. The aim of this study was to assess and compare the surgical and oncological outcomes as well as the survival rates of underweight, normal weight, overweight, and obese patients following esophagectomy for esophageal cancer. PATIENTS AND METHODS: Data relative to 1,127 patients with esophageal adenocarcinoma presenting at a specialized tertiary hospital (the Center of Esophageal Diseases for the Veneto Region) between 2000 and 2008 were prospectively collected. The 278 subjects whose BMI values before disease onset were available and underwent esophagectomy were enrolled in the study. Sixty-one of the 278 patients were classified as obese (BMI >30), 121 were classified as overweight (BMI, 25-29.9), 81 were classified as normal weight (BMI <24.9), and 15 ones as underweight (BMI <20). The outcome and survival of the four groups were compared. Frequency and survival analyses were carried out. RESULTS: The rate of R0 esophagectomy and the incidence of toxicity during neoadjuvant chemotherapy were similar in the four groups. Respiratory complications after R0 esophagectomy seemed to be more frequent in the underweight and normal-weight patients group (p < 0.01). Moreover, underweight patients had a significantly higher rate of septic, cardiovascular, and metabolic postoperative complications. The 121 overweight patients had a better overall survival rate compared to normal weight and obese patients (p = 0.05). This difference was not significant if patients were stratified in stages I or II or stages III or IV. CONCLUSION: Overweight patients seem to respond better to esophageal cancer and esophagectomy with respect to normal-weight ones. This data seem to suggest that in spite of several unfavorable features, a moderate increase of weight may be helpful to survive after esophagectomy for cancer.
Asunto(s)
Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/cirugía , Esofagectomía , Sobrepeso , Anciano , Neoplasias Esofágicas/complicaciones , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sobrepeso/complicaciones , Estudios Prospectivos , Tasa de SupervivenciaRESUMEN
BACKGROUND: Free fatty acids (FFAs) acutely stimulate but chronically impair glucose-stimulated insulin secretion from beta-cells. The G protein-coupled transmembrane receptor 40 (GPR40) mediates both acute and chronic effects of FFAs on insulin secretion and plays a role in glucose homeostasis. Limited information is available on the effect of GPR40 genetic abnormalities on insulin secretion and metabolic regulation in human subjects. STUDY DESIGN AND RESULTS: For in vivo studies, we screened 734 subjects for the coding region of GPR40 and identified a new single-nucleotide mutation (Gly180Ser). The mean allele frequency was 0.75%, which progressively increased (P < 0.05) from nonobese subjects (0.42%) to moderately obese (body mass index = 30-39.9 kg/m2, 1.07%) and severely obese patients (body mass index > or = 40 kg/m2, 2.60%). The relationship between the GPR40 mutation, insulin secretion, and metabolic alterations was studied in 11 Gly/Ser mutation carriers. In these subjects, insulin secretion (insulinogenic index derived from oral glucose tolerance test) was significantly lower than in 692 Gly/Gly carriers (86.0 +/- 48.2 vs. 183.7 +/- 134.4, P < 0.005). Moreover, a case-control study indicated that plasma insulin and C-peptide responses to a lipid load were significantly (P < 0.05) lower in six Gly/Ser than in 12 Gly/Gly carriers. In vitro experiments in HeLa cells cotransfected with aequorin and the mutated Gly/Ser GPR40 indicated that intracellular Ca2+ concentration increase after oleic acid was significantly lower than in Gly/Gly GPR40-transfected cells. This fact was confirmed using fura-2 acetoxymethyl ester. CONCLUSIONS: This newly identified GPR40 variant results in a loss of function that prevents the beta-cell ability to adequately sense lipids as an insulin secretory stimulus because of impaired intracellular Ca2+ concentration increase.